U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document



### SCREENING

- LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS

2

- Amino

- 2

- methyl

- 1

- propanol (AMP)

CASRN 124

- 68

- 5

The High Production Volume (HPV) Challenge Program 1 was conceived as a voluntary initiative aimed at developing and making publicly available screening

- level health and environmental effects information on chemicals manufactured in or imported into the United States in quanti ties greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsored chemicals; sponsorship entailed the identification and initial assessment of the adequacy of existing toxicity data/inf ormation, conducting new testing if adequate data did not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to “SIDS” (Screening Information Data Set 1, 2 ) endpoints that are screening

- level indicators of potential hazards (toxicity) for humans or the environment.

The Environmental Protection Agency’s Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Chall enge Program on approximately 1400 sponsored chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. They are not intended to be definitive statements regarding the possibility of unreasonable risk of injury to health or the environment.

The evaluation is performed according to established EPA guidance 2

, 3 and is based primarily on hazard data provided by sponsors; however, in preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor’s responses to comments and revisions made to the submission. In order to determine whether any new hazard information was developed since the time of the HPV submission, a search of the following databases was made from one year prior to the date of the HPV Challenge submission to the present: ( ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, ATSDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.) and Science Direct

. O PPT’s focus on these specific sources is based on their being of high quality, highly relevant to hazard characterization, and publicly available.

OPPT may not develop HCs for those HPV chemicals which have recently been assessed and published internati onally through the HPV program of the Organization for Economic Cooperation and Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are presented in an international forum that involves review and endorsement by

1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm

. 2 U.S. EPA. HPV Challenge Program

– Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm

. 3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm

.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

2 governmental authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening

- level hazard assessments. HCs may be created if new data suggest a need to update the case work where the OECD document will be used as key support documentation.

These hazard characterizations are technical documents intended to inform subsequent decisions and actions by OPPT. Accordin gly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and may provide information previously not readily

av ailable to the public.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

3 Chemical Abstract Service Registry Number (CASRN) 124

- 68

- 5

Chemical Abstract Index

Name 1

- P ropanol , 2

- amino

- 2

- methyl

Structural Formula

Summary

2

- Amino

- 2

- methyl

- 1

- propanol (AMP) is a solid possessing low vapor pressure and high water solubility. It is expected to have high mobility in soil. The rate of volatilization is considered low based on its Henry’s Law constant. Under normal environmental conditions, AMP will not undergo hydrolysis because there are no hydrolyzable groups in its structure. The rate of atmospheric oxidation is negligible. AMP is not readily biodegradable. It is expected to have low persistence (P1) in water , soil and air, m oderate persistence (P2) in sediment, and low bioaccumulation potential (B1).

The acute oral and dermal toxicity of AMP is low in male rats and rabbits (both sexes), respectively. In a 90

- day repeated dose toxicity study, rats were administered AMP by ora l gavage at pH 7 and pH 11

. At pH 11

, mortality was observed at the two high doses; the NOAEL

was 500 mg/kg

- bw/day . The NOAEL for pH 7 could not be determined because information was not available on the doses at which effects were observed. In an eight

- w eek dietary study in rats with AMP, hepatocyte vacuolation was observed at all doses; the severity increased with dose. Based on the hepatic effects, the NOAEL was not established

. In a similar dietary study in mice, no treatment

- related effects were obser ved at any dose; the NOAEL was 3200 ppm (highest dose tested; 14

- 28 mg/kg

- bw/day)

. In a 90

- day dietary study in dogs with AMP

, f indings were largely indicative of the liver as a target organ

. B ased on increased liver weights with associated histopathologi cal findings and clinical chemistry changes at the two higher doses , t he NOAEL was 25 ppm (~0.9 mg/kg

- bw/day). In a one

- year dietary dog study using AMP, clinical chemistry findings for high

- dose males included differences in serum albumin via

serum electrophoresis, but no related differences were seen by clinical chemistry measurements ; t he NOAEL was 110 ppm (highest dose tested ; ~3 mg/kg

- bw/day ).

I n a reproductive / developmental toxicity screening test

, dietary exposure of rats to AMP showed complet e litter resorption (100% post

- implantation loss) at 1000 mg/kg

- bw/day, and significant resorptions at 300 mg/kg

- bw/day. Effects associated with, or secondary to the post

- implantation loss increase at 300 mg/kg

- bw/day included decreased litter size, increa sed mean pup body weight, and decreased gestation body weight and body weight gain. In males, liver effects (weight changes and microscopic) were observed at 1000 mg/kg

- bw/day. T he NOAEL for systemic toxicity in males was 100 mg/kg

- bw/day, but could not b e established for females due to liver effects in the low dose group; the NOAEL for reproductive/developmental toxicity wasU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

4 100 mg/kg

- bw /day. In a mechanistic study, the authors suggested that increases in post

implantation loss and liver effects seen at 300 mg/kg

- bw/day (67% vs. 7.4% in controls) might be a result of decreased phosphocholine. In a prenatal developmental toxicity study, rats dermally treated with AMP exhibited irritation at the application site (high incidence of scabbing and scaling), pa rticularly at 300 mg/kg

- bw/day, but there was no evidence of AMP

- related systemic maternal or developmental toxicity at any treatment dose. The NOAEL for maternal toxicity was 100 mg/kg

- bw/day and for developmental toxicity, 300 mg/kg

- bw/day (highest dose tested). AMP did not induce gene mutations in bacteria or mammalian cells in vitro and did not induce micronuclei in mice in vivo

. AMP is irritating to the skin and the respiratory tract in mice and a severe irritant to the eyes of rabbits

. AMP is not a skin sensitizer in guinea pigs.
For AMP, t he 96

- h LC 50 acute toxicity to fish ranges from 184

- 190 mg/L (nominal). The acute toxicity for aquatic invertebrates 48

- h EC 50 is 193 mg/L (nominal) and the toxicity to aquatic plants 72

- h EC 50 growth rate is 520 mg/L (nominal).

No data gaps were identified under the HPV Challenge Program.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

5 The sponsor, the Dow Chemical Company, submitted a Test Plan and Robust Summaries to EPA for 2

- amino

- 2

- methyl propanol for consideration in the OECD /ICCA HPV program. O n August 18 , 20 11, EPA received a written request from the sponsor to move sponsorship of AMP to the EPA HPV Challenge Program . EPA posted the submission on the ChemRTK HPV Challenge website on November 7

, 2011 ( http://www.epa.gov/chemrtk/pubs/summaries/2

- amino

- 2

- meth

prop/c16861tc.htm )

.

1

. C hemical Identity

1.1 Identification and Purity

The compound is sold as a reaction product; water is the only additive in the c ommercial product. Although AMP may include up to 8% impurities, analysis of commercial AMP did not detect nitrosamines (< 50 ppb) or other compounds ( Dow Chemical Company , 2003; Angus Chemical Company, 2007; Estrin et al., 1982).

1.2 Physical

- Chemical Properties

The physical

- chemical proper ties of the 2

- amino

- 2

- methyl propanol are summarized in Table 1.

Table 1

. Physical

- Chemical Properties of 2

- A mino

- 2

- methyl propanol 1 Property SPONSORED CHEMICAL 2

- A mino

- 2

- methyl propanol CASRN 124

- 68

- 5 Molecular Weight 89.14 Physical State Solid crystalline mass or viscous liquid (commercial product) Melting Point 30 °C (measured) Boiling Point 165.5 o C at 1013 hPa (measured) Vapor Pressure 0.45 hPa to 1.33 hPa at 20 o C (measured)
Dissociation Constant (pK a ) Not applicable Henry’s Law Constant 6.57 X 10 - 5 Pa

- m 3 /mol (estimated) 2 Water Solubility Miscible at 25 o C Log K ow - 0.63 at 20 o C (measured)

1 The Dow Chemical Company Revised Robust Summary. Available online at: http://www.epa.gov/chemrtk/pubs/summaries/2

- amino

- 2

- meth

- prop/c16861tc.htm , November 7, 2011.
2 U.S. EPA. 2011. Estimation Programs Interface SuiteTM for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at : http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htmU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

6 2. General Information on Exposure

2.1 Production Volume and Use Pattern

CASRN 124

- 68

- 5 had an aggregated production and/or import volume in the United States between 10 million and 5 0 million pounds during calendar year 2005.

Industrial processing and uses, and commercial and consumer uses for the chemical were claimed confidential.

2.2 Environmental Exposure and Fate

T he environmental fate properties are provided in Table 2

.

2

- Amino

- 2

- methyl propanol does not absorb light at >290 nm, and therefore direct photolysis is not possible. However, i ndirect photolysis (hydroxyl radicals) is possible. The half

- life based on hydroxyl radical attack of AMP was found to be 4 hours. A MP does not possess a molecular structure that contains functional groups subject to hydrolysis under neutral ambient conditions, and is reported to be stable indefinitely at <200 o C.

AMP is not “readily biodegradable” as indicated in a closed bottle test. However, some degradation has been shown to occur under favorable conditions based on measured mineralization in soil and activated sludge

. The bio concentration factor of 14 C

- AMP was determined experimentally in G o lden orfe ( Leuciscus idus ) , and was reported to be less than 1. B io accumulation is not expected based on the partition coefficient and very high water solubility.

At environmental pH (typically pH 8) AMP is highly water soluble and hygroscopic, and in w ater is present primarily protonated (as an ammonium ion ), with chloride, hydroxide or other available environmental anion as the counter ion. AMP is also known to readily form carbonate salts by reacting with carbon dioxide in the air. It would be expec ted that much of the AMP would ionize to form salts in the environment.

Table 2

. Environmental Properties of 2

- A mino

- 2

- methyl propanol 1 Property SPONSORED CHEMICAL 2

- A mino

- 2

- methyl propanol CASRN 124

- 68

- 5 Photodegradation Half

- life 4 hours ( measured ) Hydrolysis Half

- life Contains no functional groups subject to hydrolysis under neutral ambient conditions; stable at < 200 o C Biodegradation 40 % degradation in 28 days ( Not readily biodegradable

– OECD TG 301D) ; 89.3 % degradation in 28 days ( Readily b iodegradable

– OECD TG 301F ) Bioaccumulation Factor 0.9 (estimated) 2 Log K oc 2.54 (estimated) 2U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

7

Table 2

. Environmental Properties of 2

- A mino

- 2

- methyl propanol 1 Property SPONSORED CHEMICAL 2

- A mino

- 2

- methyl propanol Fugacity (Level III Model) 2 Air (%) Water (%) Soil (%) Sediment (%) 0.0146

36.2 63.7 0.07 Persistence 3 P1 (Not persistent in water, soil or air ) 3
P2 (Moderately persistent in sediment) 3
Bioaccumulation 3 B1 (Not bioaccumulative) 3

1 The Dow Chemical Company Revised Robust Summary. Available online at: http://www.epa.gov/chemrtk/pubs/summaries/2

- amino

- 2

- meth

- prop/c16861tc.htm , November 7, 2011

. 2 U.S. EPA. 2011. Estimation Programs Interface SuiteTM for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available onl ine from: http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm
3 Persistence and bioaccumulation estimations and criteria are available in the PBT Profiler website, available online
at: http://www.pbtprofiler.net [See Appendix]

Conclusion: 2

- Amino

- 2

- methyl

- 1

- propanol (AMP) is a solid possessing low vapor pressure and high water solubility. It is expected to have high mobility in soil. The rate of volatilization is considered low based on its Henry’s Law constant. Under normal environmental conditions, AMP will not undergo hydrolysis because there are no hydrolyzable groups in its structure. The rate of atmospheric oxidation is negligible. AMP is not readily biodegradable. It is expected to have low persistence (P1) in water, soil and air, m oderate persistence (P2) in sediment, and low bioaccumulation potential (B1).

3

. Human Health Hazard

A summary of health effects data submitted for SIDS endpoints is provided in Table 3

.

Acute Oral Toxicity

AMP was administered as a single dose in physiological saline to young male rats (10/dose) at 2200

- 4000 mg/kg. Rats were observed for 14 days. Signs of acute toxicity included labored breathing, ataxia, and death due to respiratory collapse. There was gross l y observable damage noted to the liver, kidney, spleen, and respiratory system, and doses greater than 2800 mg/kg produced irritation to the stomach and duodenum. Upon necropsy, a dark clot was seen in the heart. An oral LD 50 of 2900 mg/kg was determined

. LD 50 (male) = 290 0 mg/kgU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

8 Acute Dermal Toxicity

Undiluted AMP was applied to intact and abraded rabbit (male and female/4 animals/dose) skin at 1000, 1500 or 2000 mg/kg for 24 hours under occluded dressings and observed for 14 days. There were no signs of systemic toxicity . H owever the treatment sites were necrotic within 2

- 3 days, and remained so at study termination. AMP was considered to be a severe skin irritant. Treated groups exhibited a loss in body weight over the 14

- day post

- treatment pe riod. T he LD 50 was reported to be greater than 2000 mg/kg. LD 50 > 2000 mg/kg

Repeated

- D ose T oxicity

(1) In a 90

- day oral gavage repeated

- dose study, CD rats (male and female) were gavaged with 0, 500, 750, 1100 or 1700 mg/kg

- bw/day AMP for 5 days/week at both pH 7 and 11. At pH 11, decreased survival was seen at all doses, and no animals survived at 1700 mg/kg

- bw/day. Abdominal swelling was seen in pH 11 rats at 1100 and 1700 mg/kg

- bw/day; all these rats later died. No treatment

- related mor tality was seen in the pH 7 rats. Clinical signs of toxicity (e.g. hyperventilation, hyperirritability, hyperactivity, convulsions, and neuromuscular paralysis) were noted largely in the animals given pH 11 AMP, but to a lesser extent in pH 7 AMP as well. Skin exfoliation and some ulceration as well as hair loss were seen. Nasal and mouth bleeding was also noted. The lowest dose(s) at which these symptoms were observed were not stated. There were no significant differences in body weights. AMP

- administ ered rats appeared to drink more frequently than controls. Neither the pH 7 nor the pH 11 females showed significant differences in hematocrit, hemoglobin, erythrocyte counts, or leukocytes. The males from the pH 11 group in the 1100 mg/kg dose group sho wed a significant decrease in hematocrit and hemoglobin, and red blood cell count due to a loss of blood; red blood cell counts were also decreased at all other pH 11 doses but statistical significance was not stated. pH 11 rats showed increased white blo od cells without a clear dose response. In the pH 7 rats, decreased hematocrit and hemoglobin was seen at 1700 mg/kg

- bw/day. Also at pH 7, alanine aminotransferase was increased at 1100 mg/kg

- bw/day (males) and 1700 mg/kg

- bw/day (both sexes). Urinalysis was conducted only for the pH 11 rats. Some proteinuria was seen, but doses were not noted. There were no treatment

related grossly

- recognizable changes observed at necropsy. Because the authors do not state doses at which other effects were observed, t he LOAEL and NOAEL could not be determined for the pH 7 groups. LOAEL = 50 0 mg/kg

- bw/day (based on mortality ) NOAEL = Not established

(2) In a 90

- day oral repeated

- dose study, beagle dogs (4/sex/dose) were fed 25, 600 or 2500 ppm (approximately 0.9, 22, and 90 mg/kg

- bw/day) AMP in the diet (Parekh, 1981). Body weight was decreased by 10% at the highest dose, although the change was not statistically significant. Decreased hemoglobin was seen in females at the highest dose (p < 0.05) with similar trend a t lower doses and decreased prothrombin time was seen in males at the mid and high doses (p < 0.01). The authors noted clinical chemistry changes (higher bilirubin, lower cholesterol, and elevations of aspartate aminotransferase

, alanine aminotransferas e , and alkaline phosphatase), increased liver weights, and histopathologic findings (vacuolization, periportal cirrhosis, and bile duct hyperplasia) at the 2500 ppm dose level in the diet (approximately 90 mg/kg

- bw/day) thatU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

9 are indicative of the liver as a target organ. At the mid and high dose, increased relative and absolute kidney weights were seen but without accompanying changes in urinalysis. LOAEL = 600 ppm ( 22 mg/kg

- bw/day; based on prothrombin time in males, increased liver and/or liver:body we ight ratios in both sexes, and minimal fatty changes in the liver ) NOAEL = 25 ppm (0.9 mg/kg

- bw/day)

(3) In an eight

- week oral repeated

- dose study

, Sprague

- Dawley rats ( 10/sex/dose) were fed 0, 10 00, 2000, 4000, 8000 or 16,000 ppm AMP (mixed with distill ed water) in the diet. The corresponding approximate doses by body weight (males/females) were determined to be 0, 244/436, 474/806, 912/1628, 1901/3424, and 4698/7579 mg/kg

- bw/day, respectively. R ats were observed for changes in general behavior and app earance each day, and b ody weights and food consumption were recorded weekly. All control rats, surviving rats at the top two doses and two rats/sex at each of the other doses were necropsied at the end of the study. Livers and gross lesions were examine d microscopically. At the high dose, several effects were seen in rats. Rough hair coat, emaciation, and scattered lesions over the dorsal surfaces of a few rats were seen at week three, with all rats showing similar clinical signs after the third week. Dorsal hair loss was seen starting at week five . Two female rats died during the study; one of these exhibited tremors and paleness. These rats gained slightly less weight compared to controls. At necropsy, alopecia and focal skin erosions and ulcerations as well as microscopic skin lesions were viewed as possibly compound related. In all treatment groups, hepatocyte vacuolation was seen in rats, with increasing severity at the higher dose s. LOAEL = 100 ppm ( 244/436 mg/kg

- bw/day in males/fema les; based on hepatocyte vacuolation seen at all doses ) NOAEL = Not established

(4) In a similar eight

- week oral repeated

- dose study, CD

- 1 mice ( 10/sex /dose ) were fed 0, 200, 400, 800, 1600 or 3200 ppm AMP (mixed with distilled water) in the diet. These doses corresponded to approximate doses by body weight (males/females), of 0, 1.2 / 1.6, 2.1 / 3.1, 3.4 / 6.1, 9.0 / 13, and 14 / 28 mg/kg

- bw/day. M ice were observed for changes in general behavior and appearance , b ody weights and food consumpt ion. All surviving mice at the 3200 ppm dose and 2 rats per sex at each of the other doses and in controls were necropsied at the end of the study. Livers and gross lesions were examined microscopically. No compound

- related changes were seen at any treatment dose

. NOAEL = 3200 ppm (14

- 28 mg/kg

- bw/day; based on no treatment

- related effects observed at highest dose tested)

(5) In a one

- year oral repeated

- dose study, b eagle dogs were treated with AMP in the diet at 0, 1.1, 11 and 110 ppm (approx imate ly 0.029/0.031, 0.31/0.31, and 2.6/3.0 mg/kg

- bw/day in females/males). General behavior, appearance, and body weight was recorded, and ophthalmoscopic examinations were conducted. Full clinical chemistry, hematology, urinalysis and pathological examinati ons were conducted. Clinical chemistry findings for males revealed a slight decrease in the low and mid

- dose groups' albumin

- globulin ratio. Since there was no clear dose

- response in any clinical chemistry finding (the high dose group was not different th an the control), the findings were judged to be spurious findings and not treatment

- related. At 9 and 12 months, high

- dose males exhibited differences in serum albumin via serum electrophoresis, but clinical chemistry measurements did not show differences , and was not considered by the authorsU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

10 to be biologically

- significant. Throughout the study, findings for females included differences in serum sodium, serum alanine aminotransferase, and serum aspartate aminotransferase, but were transient, did not appe ar dose

- related, and were judged by the authors to be not related to the administration of AMP

. NOAEL = 110 ppm (2.6

- 3.0 mg/kg

- bw/day; based on no treatment

- related effects observed at highest dose tested)

Reproductive Toxicity

In a combined reproductive/developmental toxicity guideline study , CD rats (12/sex/dose) were fed diets supplying 0 (control), 100, 300 or 1000 mg/kg

- bw/day AMP. Males were exposed for at least two weeks prior to breeding and continuing through out breeding for 37 days. The females were exposed for two weeks prior to breeding, continuing through breeding (up to two weeks), gestation (three weeks), and lactation (four days). Effects on gonadal function, mating behaviour, conception, development of the conceptus, parturition, litter size, pup survival, sex, pup body weight, pup gross external morphological alterations, and pathology of adult gonads were assessed. At 1000 mg/kg

- bw/day, i ncreases in absolute and relative liver weights, accompanied by a very slight degree of microvacuolization of periportal hepatocytes, with or without vacuolization of hepatocytes were noted in males . Females in all treatment groups exhibited similar histopathological changes in the liver with greater frequency , but in the absence of an organ weight change. AMP had no effect on mating performance or conception, but caused marked, dose

- related increases in post

- implantation loss (embryo resorption). At the high est dose, all 12 pregnant females showed 100% post

- impla ntation loss, while at 300 mg/kg

bw /day, post

- implantation loss was 70% (vs. 10% in controls). Effects associated with, or secondary to the increase in post

- implantation loss increase at 300 mg/kg

- bw /day included decreased litter size, increased mean pup body weight, and decreased gestation body weight and body weight gain in dams . There were no treatment related effects on reproductive performance in the 100 mg/kg

- bw /day group. LOAEL ( male systemic toxicity) = 1000 mg/kg

- bw/day (based on liver effects) NOAEL ( male systemic toxicity) = 300 mg/kg

- bw/day LOAEL (female systemic toxicity) = 1 00 mg/kg

- bw/day (based on the presence of microscopic liver effects at all doses) NOAEL (female systemic toxicity) = Not established LOAEL (reproductive toxicity) = 300 mg/kg

- bw/day (based on post

- implantation loss) NOAEL (reproductive toxicity) = 100 mg/kg

- bw/dayU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

11 Developmental Toxicity

(1) In the combined reproductive/developmental toxicity study in rats, described above, post implantation loss was observed at doses of 300 mg/kg

- bw/day and above. Liver effects were observed in dams at all doses. LOAEL ( maternal toxicity) = 1 00 mg/kg

- bw/day (based on the presence of microscopic liver effects at all doses) NOAEL ( maternal toxicity) = Not established LOAEL ( developmental toxicity) = 300 mg/kg

- bw/day (based on post

- implantation loss) NOAEL ( developmental toxicity) = 100 mg/kg

- bw/day

(2) In a prenatal developmental toxicity study, pregnant rats were exposed 6 hours daily via the dermal route to 0, 30, 100, or 300 mg AMP/kg

- bw/day from gestation days (GD) 6

- 20. Rats were sacrificed on GD 21, and subjected to a pathological examination including external tissues and all orifices , s tomach, liver, kidneys, and uterine findings. The first four presumed pregnant fe males from each dose group were selected for blood collection on GD 20. Dermal administration of 300 mg/kg

- bw /day of AMP produced significant effects at the test site, as evidenced by scabbing and moderate to severe scaling. The dermal finding of slight scaling at 30 and 100 mg/kg

- bw /day was not considered adverse, as the observation was transient in nature and low in incidence. There was no evidence of test article

- related systemic maternal or developmental toxicity at any dose tested. T he NOAEL for ma ternal toxicity was 100 mg/kg

bw /day. The NO A EL for developmental toxicity was 300 mg/kg

- bw /day (highest dose tested )

. Analyses of blood samples confirmed systemic exposure to AMP in a dose

- responsive manner, although the study was not designed to quanti fy percent absorption. LOAEL (maternal toxicity) = 30 0 mg/kg

- bw/day ( based on high incidence of scabbing and scaling at test site ) NOAEL (maternal toxicity) = 1 0 0 mg/kg

- bw/day NOAEL (developmental toxicity) = 300 mg/kg

- bw/day (based on no adverse treatment

- related effects at the highest dose tested)

Genetic Toxicity

– Gene M utation

In vitro (1) In a bacterial reverse mutation assay using the plate incorporation method, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and E. coli (WP2 uvrA) were treated with up to 5000 μg/plate AMP (Wagner, 1996). I nitial and confirmatory assay s were used to evaluate the mutagenic potential of the test material. In triplicate tests, a minimum of 5 dose s of the test article, with vehicle (water) an d positive controls, were plated with tester strains in the presence and absence of metabolic ( rat liver S9 ) activation. Neither precipitate nor appreciable toxicity was observed in the initial or confirmatory assays. In neither the initial nor confirmat ory assay was there a positive response with any of the tester strains at any dose level, in the presence or absence of S9 activation. The mean of each positive control exhibited at least a 3

- fold increase in the number of revertants over the mean value o f the respective vehicle control, indicating a valid test. AMP was not mutagenic in this assay.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

12 (2) In a bacterial reverse mutation assay using S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 and Saccharomyces cerevisiae (D

- 4) at test conc entrations of 0.01 to 5.0 μL/plate in both the presence and absence of metabolic activation, AMP was negative for gene mutations. A negative (solvent control) was also run. Positive controls were used and showed appropriate responses. AMP was not mutagenic in this assay.

( 3 ) In a mammalian cell gene mutation assay, L5178Y mouse lymphoma cells were exposed to the vehicle alone and solutions of AMP at concentrations of 0.5, 1.5, 5.0, 15, 50, 150, 500, 1500, 5000 μg/mL prepared in both the absence and presence of S9 (San and Clark, 1997). Positive controls, with and without S9, were tested concurrently following a preliminary assay. No treated cultures exhibited mutant frequencies more than 55 mutants per 10 6 clonable cells over the solvent control. A dose

- response trend was not o bserved in either the activated or non

activated systems, and the independent repeat of the assay showed similar results. AMP was not mutagenic in this assay

.
Genetic Toxicity

– Chromosomal Aberrations

In vivo

In a mouse micronucleus assay, ICR mice ( 5/sex/dose) received a single IP injection of 16, 30 or 60 mg/kg AMP; the positive control (cyclophosphamide) was administered in the same manner concurrently. At the scheduled sacrifice times (24 and 48 hours), marrow from the femurs was extracted and sl ides were prepared of the bone marrow cells. Using oil immersion, 2000 polychromatic erythrocytes were scored for the presence of micronuclei. The number of micronucleated normochromatic erythrocytes in the field of 2000 polychromatic erythrocytes

was en umerated. The proportion of polychromatic erythrocytes to total erythrocytes was also recorded per 1000 erythrocytes. There was no treatment

- related mortality at any dose level. Clinical signs noted on the day of dosing were limited to lethargy in males and females at 60 mg/kg (highest dose). The number of micronucleated polychromatic erythrocytes per 2000 polychromatic erythrocytes in test article

- treated groups was not statistically increased relative to their respective vehicle control in either male or female mice. AMP did not induce micronuclei in mice in this assay.

Additional Information

Skin Irritation

Rabbits were administered AMP on the clipped abdominal skin daily (and allowing the skin to dry) for 5 days. It was found to be highly irritating . Two animals had dermatitis, infiltration of skin and subcutaneous tissues, superficial redness, and loss of hair. “B urrowing ” lesions were noted when applied to wounds on abraded skin sites. AMP was highly irritating to rabbit skin.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

13 Eye Irritation

Rabbits were treated in the eye with an unknown amount of undiluted test substance. In one study, eyes were flushed 15

- 30 s after application and in the other they were not. Unflushed eyes scored the highest possible grade (110) and the flushed eyes scored 69.3 (15 sec) and 89.3 (30 sec); a score of 16 is considered a severe irritant. The damage was not mitigated even with an immediate flushing of the eyes. AMP was found to cause serious damage to the eyes and destroyed the vision when applied to rabbits. AMP was severely irritating to rabbit eyes .
Respiratory Irritation

Restrained Swiss Webster mice were head

- only exposed to 0.185 to 1

. 16 mg/ L aerosolized AMP for 3 hours followed by a 20 minute recovery period and observed for 1 week for mortality. No deaths were recorded but sensory and pulmonary irritation of mice was noted . Pulmonary irritation exhibited a delayed onset by 2

- 3 hours and didn’t fully recover 20 minutes after exposure ceased. The authors sug gested AMP caused moderate irritation. AMP was moderately irritating to rabbit eyes .

Sensitization

(1) Guinea pigs w ere treated topically with 0.5 mL of a 1 0 % AMP solution; a fter 24 hours, sites were cleaned and scored for erythema and edema according to the method of Draize. At 48 hours, AMP application was repeated, and continued 2

- 3 times per week until 10 applications were made ; after 2 applications the concentration was lowered to 5% due to mild irritation observed at the 10% applications . Animals were allowed a 2 week recovery period, and then challenged at a virgin site with 2.5% and 5% solutions of AMP (contact for 24 hours) . Sites were scored again at 3 and 48 hours

. Negative and positive controls were also used. N one of the animals induced with AMP or the vehicle control exhibited a positive response when challenged with AMP. AMP was not a dermal sensitizer in guinea pigs.

(2) Guinea pigs were administered intrad ermal injections during induction and challenge ( 0. 0 5 mL of a 1 , 0.5 and 0.1% AMP solution for inductions and 0.1mL of 0.05% and 0.01% for challenge). During the induction phase, the first injection at 1% and second injection at 0.5% AMP induced necrotic l esions, so the remaining 8 injections (administered 2

- 3 times/week) were made with 0.1% solutions. The challenge injections occurred after a 2

- week recovery period. Negative and positive controls were also used. During the challenge period, one animal i n the test group s howed mild reactions with 0.05% . In a repeat challenge, none of the animals in the test group showed any reactions with AMP

, so the material was considered to be non

- sensitizing following intradermal application. AMP was not a n intra derm al sensitizer in guinea pigs.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

14 Toxicokinetics, Metabolism and Distribution In v itro AMP was evaluated with model human and rat skin sebum using different concentrations of AMP (4 and 40%) and formulations (e.g., aqueous, lotion). At 24 hours, 6

- 17% was absorbed through human skin versus 30

- 51% through rat skin. A significant portion was lost from skin due to evaporation.

In vivo (1) The metabolism and distribution of AMP has been studied in vivo in Sprague

- Dawley rats

. Rats were administered test material ( 3 H

- AMP ) at a specific activity of 5 μCi/μmol via one int r a peritoneal injection and subsequently sacrificed at 30 minutes, and at 1, 2, 3, 6, 24, 96 hours following dosing. Serum, u rine

, and feces were collected for analysis. B rain, heart, kidney, liver, intestine, spleen, and skeletal m u scle were homogenized and analyzed for radio activity. Although a mass balance wasn’t used to determine distribution of AMP, qualitative information can be obtained from the study. Tritium appeared in the serum 30 minutes post

- dosing , and the authors noted that a large portion disappeared quickly f rom serum after initial uptake

. Low levels remained in the liver (greatest retention), skeletal muscle, heart muscle, intestines, spleen and kidneys. Hepatic radioactivity was found to be incorporated into the mitochondria and microsomal phospholipid fra ctions of liver and decreased with time

. A majority of AMP was excreted in urine (as unchanged AMP), and levels of radioactivity in urine as well as blood decreased to near background by 96 hours post dosing. (2) In a mechanistic study , two groups of six female Sprague

- Dawley rats were fed diets with 0 or 300 mg/kg

- bw/day of AMP

- HCL for two weeks before breeding, throughout breeding, and two weeks into gestation (GD 0

- 13). An increase in post

- implantation loss was seen in the dosed
group co mpared with controls (67% vs. 7.4%). The dams also showed slight increased hepatic lipid vacuolation. The changes correlated with 20

- 25% statistically

- decreased liver phosphocholine, the primary storage for choline. Two

- to three

- fold increases in glyce rophosphoholine (which indicates conversion of phosphatidyl choline to choline) were seen in the liver. The authors note that liver and post

- implantation loss effects may be a result of decreased phosphocholine.

Conclusion : The acute oral and dermal toxi city of AMP is low in male rats and rabbits (both sexes) , respectively. In a 90

- day repeated dose toxicity study, rats were administered AMP by oral gavage at pH 7 and pH 11

. At pH 11

, mortality was observed at the two high doses; the NOAEL was 500 mg/kg

- b w/day . The NOAEL for pH 7 could not be determined because information was not available on the doses at which effects were observed. In an eight

- week dietary study in rats with AMP, hepatocyte vacuolation was observed at all doses; the severity increased with dose. Based on the hepatic effects, the NOAEL was not established

. In a similar dietary study in mice, no treatment

- related effects were observed at any dose; the NOAEL was 3200 ppm (highest dose tested; 14

- 28 mg/kg

- bw/day)

. In a 90

- day dietary study in dogs with AMP , f indings were largely indicative of the liver as a target organ

. B ased on increased liver weights with associated histopathological findings and clinical chemistry changes at the two higher doses , t he NOAEL was 25 ppm (~0.9 mg/kg

- bw/day) . In a one

- year dietary dog study using AMP, clinical chemistry findings for high

- dose males included differences in serum albumin via serum electrophoresis, but no related differences were seen by clinical chemistry
measurements ; t he NOAEL was 110 ppm (hi ghest dose tested ; ~3 mg/kg

- bw/day ).U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

15 I n a reproductive / developmental toxicity screening test , d ietary exposure of rats to AMP showed complete litter resorption (100% post

- implantation loss) at 1000 mg/kg

- bw/day, and significant resorptions at 300 mg/kg

- bw/day. Effects associated with, or secondary to the post

- implantation loss increase at 300 mg/kg

- bw/day included decreased litter size, increased mean pup body weight, and decreased gestation body weight and body weight gain. In males, liver effects (weight changes and microscopic) were observed at 1000 mg/kg

- bw/day. T he NOAEL for systemic toxicity in males was 100 mg/kg

- bw/day, but could not be established for females due to liver effects in the low dose group; the NOAEL for reproductive/developmen tal toxicity was 100 mg/kg

- bw /day. In a mechanistic study, the authors suggested that increases in post

implantation loss and liver effects seen at 300 mg/kg

- bw/day (67% vs. 7.4% in controls) might be a result of decreased phosphocholine. In a prenatal d evelopmental toxicity study, rats dermally treated with AMP exhibited irritation at the application site (high incidence of scabbing and scaling), particularly at 300 mg/kg

- bw/day, but there was no evidence of AMP

- related systemic maternal or developmental toxicity at any treatment dose. The NOAEL for maternal toxicity was 100 mg/kg

- bw/day and for developmental toxicity, 300 mg/kg

- bw/day (highest dose tested)

. AMP did not induce gene mutations in bacteria or mammalian cells in vitro and did not induce mic ronuclei in mice in vivo

. AMP is irritating to skin and eyes of rabbits and the respiratory tract in mice

. AMP is not a skin sensitizer in guinea pigs.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

16 Table 3

. Summary Table of the Screening Information Data Sets Submitted under the U.S.

HPV Challenge Program

– Human Health Data
Endpoint SPONSORED CHEMICAL 2

- Amino

- 2

- methyl propanol Acute Oral Toxicity LD 50 (mg/kg) > 2000 Acute Dermal Toxicity LD 50 (mg/kg) > 2000 Repeated

- Dose Toxicity NOAEL/LOAEL Oral (mg/kg

- bw/day) (rat, 90

- day, pH11) NOAEL = not established LOAEL = 500 (rat, 8

- week) NOAEL = not established LOAEL = 244/436 ( males/females) (mouse, 8

- week) N OAEL = 14

- 28 ( highest dose tested)

(dog, 90

- day) NOAEL = 0.9 LOAEL = 22 (dog, 1

- year) NOAEL = 2.6

- 3.0 (highest dose tested)

Reproductive Toxicity NOAEL/LOAEL Oral (mg/kg

- bw/day) NOAEL=100 LOAEL=300

Developmental Toxicity NOAEL/LOAL Oral (mg/kg

- bw/day) Maternal Toxicity

Developmental Toxicity NOAEL= Not Established LOAEL= 100

NOAEL= 100 LOAEL =300 Developmental Toxicity NOAEL/LOAL Dermal (mg/kg

- bw/day) Maternal Toxicity

Developmental Toxicity NOAEL= 100 LOAEL= 300

NOAEL= 300 (not established) Genetic Toxicity

– Gene Mutation In vitro Negative Genetic Toxicity

– Chromosomal Aberrations In v ivo Negative Additional Information Skin Irritation Eye Irritation Skin Sensitization Highly irritating Severely irritating Not sensitizing
Measured data in boldU.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

17 4

. Hazard to the Environment

A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4

.

Acute Toxicity to Fish

Bluegill sunfish ( Lepomis macrochirus) were exposed to 32

- 560 mg/L (nominal concentrations) AMP under static conditions. Concentrations for the 96

- h study were based on a 72

- h range finding test using 1, 10, 100, 560 or 1000 mg/L AMP. No sublethal effects were reported. 96

- h LC 50 = 190 mg/L (nominal)

European Plaice ( Pleuronectes platessa ; 20 per dose level ) were exposed to 100, 320, 560, 1000 mg/L (nominal concentrations ) of AMP under semi

- static conditions. Nominal temperature of the test solution was 15 ° C (14.4

- 15 ° C during the test). Dissolved O 2 range during the test was 7.0

- 8.2 mg/L. The pH ran ge during the test was 8.1

- 10.3 and sali nity was 34.76

- 34.82 ‰ 96

- h LC 50 = 184 mg/L (nominal)

Acute Toxicity to Aquatic Invertebrates

(1) Daphnia magna (10/concentration) were exposed to 0, 100, 180, 320, 560 or 1000 mg/L AMP under static conditions at 19

- 20 o C. 48

- h LC 50 = 193 mg/L (nominal)

(2) Sand shrimp ( Crangon crangon ) were exposed to 0, 56, 100, 320 or 560 mg/L AMP under semi

- static conditions for 96 hours. The control mortality was 0% at 96 hours. 48

- h LC 50 = 179 mg/L 96

- h LC 50 = 179 mg/L

Toxicity to Aquatic Plants

Algae ( Scenedesmus sp

. ) was exposed to AMP (concentrations not stated) using closed vessels

. Passage of CO 2 - enriched air and variation of the air space in the test vessel allowed the optimization of growth comparable to that of an open vessel. 72

- h EC 50 (growt h rate) = 520 mg/L (nominal)

Conclusion: For AMP, t he 96

- h LC 50 acute toxicity to fish ranges from 184

- 190 mg/L (nominal). The acute toxicity for aquatic invertebrates 48

- h EC 50 is 193 mg/L (nominal) and the toxicity to aquatic plants 72

- h EC 50 growth rate is 520 mg/L (nominal).U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

18 Table 4 . Summary of the Screening Information Data Set under the U.S. HPV Challenge Program

- Aquatic Toxicity Data Endpoint SPONSORED CHEMICAL 2

- Amino

- 2

- methyl propanol Fish 96

- h LC 50 (mg/L) 184

- 190 (nominal)

Aquatic Invertebrates 48

- h L C 50 (mg/L) 193 (nominal)

Aquatic Plants 72

- h EC 50 (growth rate) (mg/L) 520 (nominal)

Bold = derived from experimental data

5

. References

Angus Chemical Company. Information about impurities in aminomethyl propanol and aminomethyl propanediol. 2007. Unpublished data submitted by CTFA. Cited in: Burnett

, C.L., Bergfeld , W.F., Belsito , D.V., Klaassen , C.D., Marks Jr , J.G., Shank , R.C., Slaga , T.J., Snyder , P.W., and Andersen , F.A. (2009) Cosmetic Ingredient Review Expert Panel. Final Amended Report on Safety Assessment on Aminomethyl Propanol and Aminomethyl Propanediol. International Journal of Toxicology, 28 ( 6) 141S

- 161S.

Estrin NF, Haynes CR, Whelan JM. (1982). CTFA Spec ifications Spectra. Washington, DC: Cosmetic, Toiletry, and Fragrance Association. Cited in: Burnett , C.L., Bergfeld , W.F., Belsito

, D.V., Klaassen , C.D., Marks Jr , J.G., Shank , R.C., Slaga , T.J., Snyder , P.W., and Andersen

, F.A. (2009) Cosmetic Ingredient Review Expert Panel. Final Amended Report on Safet y Assessment on Aminomethyl Propanol and Aminomethyl Propanediol. International Journal of Toxicology, 28 ( 6) 141S

- 161S.

Dow Chemical Company (2003). Material Safety Data Sheet.U.S. Environmental Protection Agency M arch 2012

Hazard Characterization Document

19 Appendix

PBT profiler output



### Results

Orange or red highlights indicate that the EPA criteria have been exceeded. Black

- and

- white version

Persistence Bioaccumulation Toxicity



### 124

- 68

- 5 1

- Propanol, 2

- amino

- 2

- methyl

PBT Profiler Estimate = PB T

Media Half

- Life (days) Percent in

Each Medium BCF Fish ChV (mg/l)

Water 15 39% 3.2 9.5 Soil 30 61% Sediment 140 0%

Air 0.62 0%

Developed by the Environmental Science Center under contract to the Office of Chemical Safety

and Pollution Prevention

, U.S. Environmental Protection Agency Computer Resources Donated by SRC, Inc. Ver 1.301 Last Updated November 1, 2010